The present invention provides certain novel organic compounds which have immunoregulatory properties, rendering these compounds useful in the treatment of hyperimmunity diseases. Moreover, the present invention provides for the immunoregulatory use of certain organic compounds in hyperimmunity diseases.
The novel compounds herein and the compounds employed in the novel methods herein as pharmacologic agents are all thioesters of dithiocarbanilic acid or corresponding aryl-substituted dithiocarbanilic acids. Dithiocarbanilic acid has the structural formula: ##STR1## and corresponding aryl substituted dithiocarbanilic acids include compounds of the structural formula: ##STR2## wherein T is nitro, fluoro, chloro, bromo, trifluoromethyl, lower alkylsulphonyl, phenylsulphonyl, or (lower alkyl)phenylsulphonyl; and
Wherein r is the integer 1 or 2. PA1 wherein Z.sub.1 is --C.sub.m H.sub.2m --, wherein m is the integer 1 to 5, inclusive; and .omega.-(alkoxycarbonyl) esters derived structurally from thiols of the formula EQU HS--Z.sub.1 --COOR.sub.2 IV PA1 wherein R.sub.2 is alkyl of 1 to 12 carbon atoms, inclusive; and PA1 Wherein Z.sub.1 is as defined above. PA1 wherein X is chloro, bromo, or nitro; and PA1 wherein q is the integer 0 to 5, inclusive. PA1 wherein s is the integer 0 or 1; PA1 wherein C.sub.m H.sub.2m is alkylene of 1 to 5 carbon atoms, inclusive; and PA1 wherein R.sub.2 is alkyl of 1 to 12 carbon atoms, inclusive; PA1 systemically administrating in a pharmaceutically acceptable dosage form a dithiocarbanilate of the formula ##STR8## wherein T, r, and C.sub.m H.sub.2m are as defined above, and R.sub.1 is hydrogen or R.sub.2 ;
The thioesters referred to above include .omega.-carboxyalkyl esters derived structurally from thiols of the formula EQU HS--Z.sub.1 --COOH III
Certain of the .omega.-carboxyalkyl esters of various dithiocarbanilic acids are known in the art as useful for a wide variety of purposes.
See, for example, Garraway, J. L., J. Chem. Soc. 1961: 3733 which describes the .omega.-carboxyalkyl dithiocarbanilates as precursors for the corresponding cyclic lactams (i.e., rhodanines and thiazine analogs). Further with respect to the production of rhodanine or thiazine analogs from corresponding .omega.-carboxyalkyl dithiocarbanilate precursors, see U.S. Pat. No. 3,781,434; Brown, F. C., et al., J.A.C.S. 78: 384 (1956); and Werbel, L. M., et al., J. Med. Chem. 11(2):364 (1968). The former reference describes the antiarthritic use of the cyclic thiazines, while the latter references describe the cyclic rhodanine derivations as antifungicidal, antibacterial, and antimalarial agents.
.omega.-Carboxymethyl 2,3-dihalo-dithiocarbanilates are described in British published specification No. 1,153,487 as anthelmintics. Further, U.S. Pat. No. 3,089,877 describes .omega.-(amidocarbonyl)alkyl dithiocarbonylates as fungicidal agents. Finally, U.S. Pat. No. 3,686,413 describes the anthelmintic use of dithiocarbanilates, including, inter alia, compounds of the formula ##STR3## wherein R.sub.3 is hydrogen or alkyl of 1 to 4 carbon atoms, inclusive; wherein p is the integer 1 or 2;
In addition to the uses of the dithiocarbanilates described above, certain chemical and biological investigations relating to such compounds have been undertaken and are reported in papers deposited in The California Polytechnic State University Library in San Luis Obispo, Calif. These papers are identified by author and title, as follows: Bello, J., "Some Effects of Newly Synthesized Thiocarbamates on Blood and Organ Parameters in the Mouse and Pig"; Booth, J., "The Effects of 3-(N-Meta Fluorophenyl Dithiocarbamoyl) Propanoic Acid on BAPN Induced Lathyrism in the Rat"; Burdick. P. R., "Warfarin Activity Modification and Other Effects of Some New Thiocarbamates in Mice"; Foster, R., "Modification of the Erythrocyte Membrane in Swine"; Jones, P., "Histological Effects of Carbamate Derivatives on the Spleen and Thymus of Swiss-Webster Mice"; Lash, L. D., "Leukocyte Depression and Other Responses in the Mouse, Produced by Datisca and a Novel Thiocarbamate"; Meyer, O., "The Effects of 3(N-Metafluorophenyl)Dithiocarbamoyl Propanoic Acid on the Lathrytic Condition Induced by Beta-Aminoproprionitrile"; Mortensen, M. L., "The Synthesis of Some of the Reaction Products of Isocyanates and Isothiocyanates with 3-Mercaptopropionic Acid"; and Reid, A., "Modification of Lathyrism in Rats by Three New Thiocarbamates."
Immunoregulatory agents may be either immunosuppressive or immunostimulatory. For the purposes of the present invention immunoregulation shall make reference to the process of immunosuppression in response to a disease or other condition resulting from hyperimmunity in the animal or patient. For a comprehensive review of the use of immunosuppressive agents in the treatment of hyperimmunity diseases, see Camiener, G. W., et al., Progress in Drug Research 16:67 (1972) and Wechter, W. J., et al., Progress in Drug Research 20:573 (1976).
Many known immunosuppressive agents are cytotoxic and are believed in part to accomplish the immunosuppressive effects via a cytotoxic mechanism on the immunoactive organs (e.g., bone marrow and thymus). For example, the known antineoplastic agent, cyclophosphamide, has been used in the treatment of arthritis. See Skinner, M. D., et al., Rheumatology 5:1 (1974).
Finally, anthelmintics such as niridazole have been employed immunosuppressively to control allograft rejection; while another anthelmintic, levamisole, is apparently a non-specific stimulator of the immune system. See Daniels, J. D., et al., J. Immun. 115:1414 (1975) and Renorex, G., et al., J. Immun. 109:761 (1972).